Prolonged hypergastrinemia causes proliferation of gastric enterochromaffin-like cells (ECL cells) which can progress to the development of carcinoid tumors, some of which are malignant. With their increased chronic use in such common conditions as gastroesophageal reflux disease (GERD), with H-+-K-+ ATPase inhibitors (omeprazole, etc.), which are potent acid suppressants and can cause hypergastrinemia in >80% of patients, there is increased concern over the longterm effects on gastricECL cells in humans. Currently, it is unclear in humans, the time course of changes with hypergastrinemia in ECL cells, their severity with prolonged treatment, factors that contribute to carcinoid development or the best means to identify gastric carcinoids. Patients with Zollinger-Ellison syndrome (ZES) have life-long hypergastrinemia because most are not cured and therefore are excellent models to study these gastric effects. Furthermore, 25% of patients with ZES have MEN-1 which predisposes them to the development of gastric carcinoids and hence have accelerated development of these tumors. To address the frequency and severity of gastric ECL changes that occur with chronic hypergastrinemia, the frequency of carcinoid tumors, the best methods to detect them and the identification of contributing factors, a series of long-term prospective studies have been started in collaboration with Prof. C. Bordi, Dept. of Pathology, Univ. of Pharma, Italy and Prof. G. Delle Fave, La Sapienza, Rome, Italy. The first study was recently completed which involved systematic gastric biopsies at regular intervals from 8 fixed areas in the stomach on a large cohort of patients with ZES to determine the best areas to biopsy and variability of results in different gastric areas. Furthermore, similar studies are being performed on patients with chronic atrophic gastritis, which also results in chronic hypergastrinemia, normals for comparison and patients with MEN-1 without ZES. All biopsies are analyzed for changes in the ECL cells, the degree of inflammation, morphologic changes and changes in other proteins that may parallel the extent of ECL changes or contribute to their proliferation such as the expression of alpha-HCG. This first study demonstrates gastric biopsies assessing gastric ECL changes should be from the greater curvature; a single biopsy is satisfactory for qualitative ECL assessment but frequent biopsies are needed to detect carcinoid tumors. All high risk patients are undergoing gastric endoscopic ultrasonography (EUS) to attempt to localize carcinoid tumors. Comparison of the ability of biopsy, endoscopy and EUS to assess advanced ECL changes and the location and extent of gastric carcinoid tumors will be possible from this study. As of October, 2000, 218 patients have been entered into this study most biopsied on multiple occasions. This study will allow definition of the time course and extent of ECL changes. Currently, the second study on extent and determinants of the ECL changes in patients with the sporadic form of the disease is almost completed and will be analyzed this year.